A heart attack patient’s blocked artery has just been reopened by a stent, but in up to half of cases, tiny clots and damaged vessels still starve the heart muscle of blood—a condition called microvascular obstruction (MVO) that doubles the risk of heart failure and early death. No treatment currently exists for MVO. This trial tests whether a very low dose of the clot-busting drug alteplase, delivered directly into the coronary artery during the stenting procedure, can dissolve those residual microclots and restore blood flow at the capillary level. The researchers will give 618 high-risk patients either a placebo, 10 mg, or 20 mg of intracoronary alteplase, then measure MVO on MRI scans two days later, along with ECG changes, heart function, and bleeding complications over 15 months. If the drug safely reduces MVO, it could become a simple, cheap addition to standard heart attack care—a single injection during an already routine procedure—potentially preventing thousands of cases of heart failure each year without requiring new equipment or training.
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STEMI causes heart failure and premature death. Whilst primary PCI to open the blocked coronary artery saves lives, 40-50% of STEMI patients have microvascular obstruction (MVO). Fibrin-rich microthrombi and microvascular injury cause MVO which is delineated by magnetic resonance imaging (MRI). MVO is prognostically important since it is an independent predictor of heart failure and reduced survival so increasing the public health burden of MI. There are no evidence-based treatments for MVO. Our proposal is novel and unique since it is the first in primary PCI to target fibrin with direct lysis of fibrin-rich microthrombi in the culprit artery. AIM: To evaluate if low dose intracoronary fibrinolysis given initially after mechanical reperfusion can reduce MVO and improve clinically-important surrogate measures of cardiac outcome. Full dose I.V. alteplase (100 mg) is an effective fibrinolytic but confers a dose-related risk of bleeding and as a stand-alone therapy is inferior to primary PCI (standard care). OBJECTIVE: To evaluate the efficacy, mechanisms, and safety of reduced dose intracoronary alteplase when given during primary PCI in high-risk STEMI patients. The circulating half life of alteplase is 5 min but its ‘deep tissue’ beta half life is ~40 min (local delivery avoids hepatic first-pass clearance). Therefore, we will conduct a placebo-controlled dose-ranging trial of very low (1/10th; 10 mg) or low (1/5th; 20 mg) dose intra-coronary alteplase given after mechanical reperfusion at the start of PCI in 618 patients (206/group). HYPOTHESES: Local intracoronary delivery of alteplase upstream of the culprit lesion will lyse persistent & de novo fibrin-rich thrombus and so reduce and prevent MVO. Low dose alteplase will be safe. PLAN: A randomised parallel group double blind placebo-controlled dose ranging Phase II trial of intracoronary alteplase in 618 STEMI patients with an occluded artery (a marker of increased risk) treated 6 hrs from symptom onset. T-TIME will take place simultaneously in 8 UK hospitals (~80 patients/site; Site Feasibility Assessments done). Recruitment/consent will be lead by the Consultant Cardiologist. SAFETY, early efficacy of reperfusion, surrogate outcome measures will be prospectively evaluated and a health economic evaluation will also be performed. STUDY DRUGS: Alteplase and identical placebo will be given in a double-blind manner by slow manual infusion using a flushed aspiration catheter. The trial will include 3 groups (pre-prepared packs): (1) placebo, (2) alteplase 10 mg, (3) alteplase 20 mg, at the start of PCI only. The Primary Efficacy Outcome is extent of late MVO (% of LV mass) 2 days post-MI, which is prognostically-validated surrogate outcome. MVO is defined as a dark zone of persistent hypoenhancement with signal intensity >2SDs lower than the bright hyperenhanced myocardium with late gadolinium MRI. Secondary measures of alteplase effect will be studied: Acute: ECG (residual ST elevation), angiographic blush grade, TIMI frame count, thrombus score (change in thrombus score post- vs. pre-study drug); 2 days: MRI (MVO on 'first pass' contrast MRI, myocardial salvage, infarct size, LV function & volumes); 3 months: MRI, NT-BNP. Blood will be collected in the first 24h post-MI for coagulation markers of alteplase mechanisms & safety. The cardiologists will complete a questionnaire for feasibility and safety of study drug administration. Health outcomes (death, bleeding, stroke, MI and heart failure) for safety will be prospectively collected (mean Fup 15 months). Quality of life (EQ-5D; SF-36) at baseline, 3 & 12 months will be assessed and a health economic evaluation will be done. SAMPLE SIZE: n= 618 patients will be recruited (206 subjects / group): 1. Placebo; 2. Alteplase 10 mg; 3. Alteplase 20 mg. With a minimum of 186 patients in each group, there would be 80% and 90% power at a 5% level of significance to detect between-group mean differences of 1.49% or 1.72% respe
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